Van Der Putten Research Articles

The long view of vaccination to secure the future

The long view of vaccination to secure the future

306 (PB086) - Reversal of resistance to docetaxel and cabazitaxel in prostate cancer cells with ritonavir

Background: The taxanes docetaxel and cabazitaxel are indicated for treatment of metastatic castration-resistant prostate cancer (mCRPC). Resistance to docetaxel often develops during treatment, which can be due to an increased efflux of docetaxel via P-glycoprotein (P-gp) from the intracellular site of action. Ritonavir is an inhibitor of both cytochrome P4503A4 (CYP3A4) and P-gp. In this study we investigated whether ritonavir could improve the efficacy of docetaxel through inhibition of P-gp in docetaxel-resistant prostate cancer cells. Methods: Prostate cancer cell lines DU-145 and 22Rv1 were exposed to increasing doses of docetaxel to generate resistant sublines, DU145-DOC10 and 22Rv1DOC8 respectively. Gene expression of the resistant clones was compared to that of the parental cell lines. The parental cell lines and the docetaxel resistant cell lines were treated with several drug combinations in an 8*2 matrix 3D tumor clonogenic assay. The following drug combinations were tested: docetaxel/ritonavir, docetaxel/elacridar and cabazitaxel/ritonavir. The IC50 values of single agent drugs and drug combinations as well as combination effects between drugs (using a Bliss independence dose-response evaluation) were determined in all cell lines. Results: The most differentially upregulated gene in the resistant cell lines was ABCB1 (P-gp). Western blotting showed that both resistant cell lines expressed more P-gp than the parental cell lines. A comparison of the observed docetaxel and cabazitaxel IC50 values has been summarized in the below table.Table(abstract: 306 (PB086))DU-145DU-145DOC10DU-145DOC1022Rv122Rv1DOC822Rv1DOC8Docetaxel IC50 (nM)2.99.52.8*with 10 μM ritonavir,1.354.63.0**with 32 μM ritonavir.Cabazitaxel IC50 (nM)0.61.50.6*with 10 μM ritonavir,0.79.50.7**with 32 μM ritonavir.* with 10 μM ritonavir,** with 32 μM ritonavir. Open table in a new tab We found that docetaxel resistance conferred cross-resistance to cabazitaxel. With the addition of 10 μM ritonavir (DU-145DOC10) and 32 μM ritonavir (22Rv1DOC8) the cytoxicity of docetaxel and cabazitaxel returned to the level of observed in the parental cell lines. A similar experiment with the specific P-gp inhibitor elacridar showed that a concentration of 0.3 μM was sufficient to reverse docetaxel resistance to the same level as in the parental cell lines, confirming this as an important mechanism-of-action. In DU-145-DOC10 and 22Rv1DOC8 cells strong synergistic effects were seen of the docetaxel/ritonavir as well as the cabazitaxel/ritonavir combination, in contrast to the lack of synergy seen in the parental cell lines with these combinations. Conclusions: We demonstrated the potential for the combination of docetaxel and ritonavir to reverse or offset resistance to docetaxel (and, by implication due to its cross-resistance, also to cabazitaxel), primarily mediated through inhibition of P-gp. This provides a strong rationale to clinically test these taxanes in combination with ritonavir in patients with mCRPC. Conflict of interest: Ownership: Jos Beijnen is a shareholder of Modra Pharmaceuticals. Board of Directors: Colin Freund and Eric van der Putten are directors of Modra Pharmaceuticals.

Abstract 1962: The relevance of estrogen driven tumor growth within the molecular subgroups of endometrial cancer

Abstract Introduction: Immunohistochemical expression (IHC) of estrogen receptor (ER) and progesterone receptor (PR) are biomarkers for prognosis and response to hormonal therapy in endometrial cancer (EC). However, the presence of ER/PR is not inherently reflective of estrogen driven tumor growth. Previously, ER pathway activity score (ERPAS), a test to asses ER pathway, was shown to reflect estrogen driven tumor growth and to have additional prognostic and predictive value over ER and PR-IHC. Within the four molecular subgroups of EC, ER and PR-IHC are present in all subgroups. Yet, the relation of ERPAS with molecular subgroups is unclear. In this study we aim to identify estrogen driven tumor growth by application of ERPAS in the molecular subgroups. Methods: ER and PR-IHC expression, ERPAS testing and molecular analysis was available in 72 endometrial cancer cases. ER and PR-IHC expression was analyzed from formalin-fixed paraffin-embedded (FFPE) tumor sections using standard procedures. A cut-off value of 10% was defined as positive. ERPAS was performed using RT-qPCR analysis of the most relevant ER-related genes (www.philips.com/oncosignal). A Bayesian computational model was used to infer ERPAS that were normalized on a scale from 0 to 100. The cut-off value for an active ER pathway was 29.7, as previously defined. Molecular analysis was performed using Next Generation Sequencing with single-molecule Molecular Inversion Probes (smMIPs). Accordingly patients were grouped in the POLE-mutant, MSI high, TP53-mutant or no specific molecular profile, NSMP group. Results: The TP53-mutant-group had a worse outcome compared to other groups. ER pathway was active in 75% of POLE-mutant, 83.3% of MSI-high, 87.5% of NSMP and 38.9% of TP53-mutant cases. Similarly, PR-IHC expression was present in 100% of POLE-mutant, 72.2% of MSI-high, 81.3% of NSMP and 27.8% of TP53-mutant cases. The mean ERPAS was significantly higher in MSI-high and NSMP groups compared to the TP53-mutant group. Within the NSMP subgroup, an active ER pathway was significantly associated with improved disease-free survival and disease-specific survival in Kaplan-Meier analysis. Analysis in other subgroups was not possible due to limited number of cases. Conclusions: The majority of POLE-mutant, MSI-high and NSMP tumors showed an active ER pathway, indicating relevance of estrogen driven tumor growth in these groups. In the NSMP subgroup, ERPAS can be used to stratify patients for prognosis. Whether ER pathway is prognostic in the MSI-high and TP53-mutant subgroups needs to be evaluated in larger cohorts. If hormonal therapy is applied, we suggest to tailor it to patient with an active ER pathway. Citation Format: Willem Jan van Weelden, Stephanie Vrede, Louis van der Putten, Hans Bulten, Marc Snijders, Sanne Sweegers, Andrea Romano, Astrid Eijkelenboom, Anja van de Stolpe, Johanna Pijnenborg. The relevance of estrogen driven tumor growth within the molecular subgroups of endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1962.

Microstructural examination of carbonated 3D-printed concrete.

The recent interest in 3D printing with concrete has generated great interest on how inhomogeneities arise and affect performance parameters, in particular strength and durability. With respect to durability, of particular interest is how 3D‐printed layer interfaces can impact transport of species of interest, such as moisture, chlorides or carbon dioxide in carbonation processes. This is of particular interest considering that the primary use case of 3D‐printed concrete has been as a lost formwork for a cast structural concrete, and thus it is of interest to determine the carbonation resistance. This study consists of a preliminary look at the microstructure after accelerated carbonation of a 3D‐printed concrete used as a lost formwork. Preferential carbonation is observed in the layer interfaces compared to the bulk of the printed filaments, possibly related to porosity from air voids or a locally high capillary porosity corresponding to the lubrication layer.

Assessing perspectives on artificial intelligence applications to gastroenterology

Assessing perspectives on artificial intelligence applications to gastroenterology

Editorial: The Next Step: Disentangling the Role of Plant-Soil Feedbacks in Plant Performance and Species Coexistence Under Natural Conditions

Effects of plant-induced changes in soil properties, which impact subsequent plant growth, have received increasing attention in plant ecology (e.g., Smith-Ramesh & Reynolds 2017). These plant-soil feedbacks (PSFs) are considered to be important for plant performance and plant-community composition in many terrestrial ecosystems (e.g., van der Putten et al. 2013). However, so far most conclusions on the importance of PSFs in natural systems have been drawn from experiments performed under highly controlled and artificial conditions. Under natural conditions, the growth and development of plants as well as that of soil organisms is influenced by many more abiotic and biotic interactions than in the greenhouse. Hence, there is an urgent need to investigate PSFs under more natural conditions and to better understand the interactions between PSFs and environmental drivers (De Long et al. 2019). This Research Topic comprises 14 articles - ranging from Original research articles, meta-analytical Reviews and Perspectives - that aim to advance our understanding of the contribution of PSFs to plant growth and plant community composition in different environmental contexts.

Greed, guns and gore: Historicising early British colonial Singapore through recent developments in the historiography of Munsyi Abdullah

Munsyi Abdullah and his better-known writings, Kisah Pelayaran Abdullah (1838) and Hikayat Abdullah (1843), are much-discussed in the historiography of early British colonial Singapore. However, Amin Sweeney's efforts to historicise some aspects of Abdullah's life and writings have established that Abdullah was much more than a sharp social critic of Malays and their rulers. He is better understood as a subtle critic and even a manipulator of his European interlocutors who craftily used his occidental contacts and connections alongside his local knowledge to preserve his role as a cultural intermediary in a burgeoning port settlement. Sweeney's efforts bring into focus a multifaceted imperial experience where notions like ‘interactions’ and ‘connections’ become viable descriptive categories in making sense of the intersections of Abdullah and empire, thereby strongly resonating with networked conceptions of imperial space propounded by ‘new’ imperial history. Taken alongside the recent literary and theoretical efforts of Jan van der Putten and Sanjay Krishnan respectively on Abdullah, and the carefully circumscribed historical efforts of Ian Proudfoot, the recent historiography of Abdullah offers fresh interpretive possibilities of early colonial Singapore. Leveraging such developments to engage with Mary Turnbull's scripting of a gruesome episode in 1823 indicates that Turnbull's historiographical dominance of Singapore's early colonial history can be transcended to better represent British coloniality, warts and all.

Soil Organisms - an international open access journal on the taxonomic and functional biodiversity in the soil.

Biodiversity change and the identification of the underlying drivers are in the focus of ecological research and public and political debate (IPBES 2019). Soil biodiversity has thus far rarely entered this discussion and analyses (Cameron et al. 2018), and substantial gaps in soil biodiversity and function data exist (Cameron et al. 2019). Furthermore, we know exceptionally little about temporal changes in soil biodiversity (Phillips et al. 2017), although soil biodiversity is thought to be essential for critical ecosystem functions and services (Bardgett & van der Putten 2014, Wall et al. 2015) but threatened by anthropogenic impacts (Veresoglou et al. 2015). At the same time, taxonomic expertise of soil biodiversity may be at risk, while novel molecular information still needs to be linked to species and functions (Geiger et al. 2016).

Intraspecific variation in litter palatability to macroarthropods in response to grazing and soil fertility

Abstract Clarifying the functional consequences of intraspecific trait variability in response to interacting trophic levels would provide a significant improvement in our understanding of above‐ground–below‐ground linkages. In particular, the effects of grazing on plant traits may translate into altered litter quality, with potentially important consequences for litter‐feeding decomposers. Plant and litter variability in response to grazing is expected to depend on soil fertility levels, with tolerance and defensive strategies more commonly expressed on fertile and poorer soils, respectively. However, how grazing and fertility interactively alter litter quality and palatability to detritivores has not been explored yet. We conducted a cafeteria experiment with three common millipede (Diplopoda) species feeding on leaf litter from two plant species, the grass Bromopsis erecta and the forb Potentilla verna. Each millipede was offered a binary choice between litter types produced by the same plant species, but sampled in plots with distinct herbivory and fertilization status: litter originating from grazed areas or from 1‐year sheep exclosures, both in native areas and in adjacent paddocks that received chemical N and P fertilization, as well as litter from a 25‐year sheep exclosures in the native area. We found that fertilization and herbivore exclusion interactively affected Bromopsis litter quality and palatability, whereas Potentilla was much less affected. Bromopsis litter palatability was not affected by grazing when litter was collected in native plots, except for the long‐term exclosure which led to low palatability. In contrast, and in line with our expectations, herbivory was associated with much higher palatability in fertilized plots. The changes in palatability were associated with important alterations of litter quality. Overall, our study demonstrates that intraspecific variation in litter can have profound consequences for soil functioning. It emphasizes the role of grazing as a key, but plant species‐specific factor controlling litter intraspecific variability, and its complex interaction with soil fertility level. Moreover, our results advocate for a better understanding of the response of the different organisms involved in the decomposition process, in particular litter‐feeding macro‐detritivores. We encourage future studies aiming at disentangling the various and complex relationships between above‐ground processes such as herbivory and soil functioning.

Abstract 2656: Estrogen receptor pathway activity in endometrial carcinomas and its relation to tumor grade and recurrence

Abstract Background Immunohistochemical (IHC) loss of expression of the estrogen (ER) and progesterone receptor (PR) from endometrial carcinomas is associated with high tumor grade, and with recurrent disease. However, expression of these receptors is not always indicative of functional pathway activity. A novel approach to predict signaling pathway activity, based on Knowledge-based Bayesian computational models interprets quantitative transcriptome data as the functional output of an active signaling pathway by using expression levels of transcriptional target genes. The objectives of this study were to compare ER pathway activity to ER and PR IHC results with respect to endometrial carcinoma grade and disease recurrences. Materials and Methods Originally for Affymetrix, the pathway analysis was adapted for RT-qPCR enabling use on FFPE tissue. Calibration and threshold definition was performed using tissue with known pathway activity. Pathway analysis was performed on: (1) A public dataset (GSE56026) containing Affymetrix expression microarray data from 62 patients with grade 1 (n=23),2 (n=17) and 3 (n=11) endometrioid and serous (n=12) carcinomas, and (2) formalin fixed, paraffin embedded (FFPE) tissue from endometrioid (n=70) and serous carcinomas (n=15), treated at the Radboud university medical center, which were immunohistochemically stained for ER and PR, and analyzed for pathway activity using qPCR. Results (1) Analysis of the public dataset showed an inverse relation between ER pathway activity score and cancer grade, with the lowest ER activity in serous carcinomas. The Mann-Whitney U test showed significant differences between grade 1 and 2 (p=0.015), grade 1 and 3 (p=0.004), and grade 1 and serous carcinomas (p<0.0001). (2) These results were confirmed in the FFPE tissue. The ER pathway was active in 30% (n=18), and inactive in 70% (n=41) of the samples. In advanced stage endometrioid and all serous carcinomas, ER pathway was active in 8% (n=2) and inactive in 92% (n=24) of the samples (Fisher p=0.03). Endometrial carcinoma related death (ECD) rate was 20% (n=17). While individually, ER pathway activity, ER and PR IHC were all significantly correlated with ECD, (logistic regression odds ratio, OR = 0.53, 0.12, 0.15, and p=0.0004, 0.0005, 0.002, respectively). In a multivariate analysis only ER pathway activity and disease stage remained significantly correlated with ECD (OR=0.52, p=0.03). Conclusion In two independent patient cohorts, the ER pathway model analysis, performed on data from Affymetrix microarrays and qPCR measurements showed an inverse relationship between the pathway activity and increasing tumor grade. While ER activity and ER/PR staining were related, only ER activity and cancer stage remained significant in a multivariate analysis with respect to immunohistochemistry alone when trying to predict recurrent disease. Citation Format: Louis J. van der Putten, Anne van Brussel, Willem Jan van Weelden, Márcia A. de Inda, Leon F. Massuger, Henk van Ooijen, Anja van de Stolpe, Johanna M. Pijnenborg. Estrogen receptor pathway activity in endometrial carcinomas and its relation to tumor grade and recurrence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2656.

Microbes matter: integrating microbial sequence information for biodiversity

The large efforts to document and map aboveground biodiversity have helped to elucidate ecological and evolutionary mechanisms and processes, predict responses to global change, and identify potential management options in response to those changes. Yet these concepts have mostly been applied to aboveground plant and animal communities, while microbial diversity remains difficult to incorporate. The ability to integrate microbial sequence data into an accessible global infrastructure has previously been limited by a few key factors: First, most of microbial diversity remains undescribed and unknown; there is just an enormous amount of biodiversity. Second, there is a lack of congruence between the many disparate microbial datasets (e.g. taxonomy, phylogeny, and methodological biases), which limits the ability to monitor and quantify global patterns of the terrestrial microbiome. Finally, there is a lack of coordination and networking between scientists studying microbes. In this presentation I will discuss two case studies that highlight how we can begin to link microbial data to the already well-established macro-knowledge and other environmental databases (like global carbon maps) Study 1 – a megameta analysis: The emergence of high-throughput DNA sequencing methods provides unprecedented opportunities to further unravel microbial ecology and its worldwide role from human health to ecosystem functioning. However, in spite of the abundance of sequencing studies, combining data from multiple individual studies to address macroecological questions of bacterial diversity remains methodically challenging and plagued with biases. While previous meta-analysis efforts have focused on diversity measures or abundances of major taxa, in a recent study(1) we show that disparate amplicon sequence data can be combined at the taxonomy-based level to assess bacterial community structure. Using a machine learning approach, we found that rarer taxa are more important for structuring soil communities than abundant taxa. We concluded that combining data from independent studies can be used to explore novel patterns in bacterial communities, identify potential ‘indicator’ taxa with an important role in structuring communities, and propose new hypotheses on the factors that shape microbial biogeography previously overlooked. Study 2 – a global soil biodiversity database: Greater access to microbial data is an important next step for biodiversity research and conservation, and for understanding the ecology and evolution of microbial communities. In collaboration with the Global Soil Biodiversity Initiative and the German Biodiversity Synthesis Centre (sDIV) we outlined steps that must be taken to ensure microbial sequence data can be included in global measures and maps of biodiversity(2). Here I will discuss how the plant associated microbiome is an optimal starting point to synthesize microbial sequence data on an open and global platform. The plant-microbiome is an optimal model system that goes across scales and time, can act as a bridge between microorganisms and macroorganisms, and as an opportunity to more thoroughly explore the synthesis of global microbial sequence data (for a global soil biodiversity database). Beyond expanding primary research, the patterns discovered in a synthesis of plant-microbiome can be used to explore and guide ecosystem restoration and sustainability. Overall, a better understanding of microbial biodiversity will help to predict consequences of (human-induced) global changes and facilitate conservation and adaptation responses. (1) Ramirez, K.S., C.G. Knight et al. and F.T. de Vries (2017). Detecting macroecological patterns in bacterial communities across independent studies of global soils. Nature Microbiology. (2) Ramirez, K.S., M. Döring, N. Eisenhauer, C. Gardi, J. Ladau, J.W. Leff, G. Lentendu, Z. Lindo, M.C. Rillig, D. Russell, S. Scheu, M.G. St. John, F.T. de Vries, T. Wubet, W.H. van der Putten, D.H. Wall, (2015). Towards a global platform for linking soil biodiversity data. Frontiers in Ecology and Evolutionary Biology 3(91). doi: 10.3389/fevo.2015.00091

ПРОСТРАНСТВЕННОЕ ВАРЬИРОВАНИЕ СОДЕРЖАНИЯ ВТОРИЧНЫХ МЕТАБОЛИТОВ, УГЛЕРОДА И АЗОТА В ПОДСТИЛКАХ СЕВЕРОТАЕЖНЫХ ЕЛЬНИКОВ*, "Лесоведение"

ПРОСТРАНСТВЕННОЕ ВАРЬИРОВАНИЕ СОДЕРЖАНИЯ ВТОРИЧНЫХ МЕТАБОЛИТОВ, УГЛЕРОДА И АЗОТА В ПОДСТИЛКАХ СЕВЕРОТАЕЖНЫХ ЕЛЬНИКОВ*, "Лесоведение"

Plant-soil feedbacks and mycorrhizal type influence temperate forest population dynamics.

Feedback with soil biota is an important determinant of terrestrial plant diversity. However, the factors regulating plant-soil feedback, which varies from positive to negative among plant species, remain uncertain. In a large-scale study involving 55 species and 550 populations of North American trees, the type of mycorrhizal association explained much of the variation in plant-soil feedbacks. In soil collected beneath conspecifics, arbuscular mycorrhizal trees experienced negative feedback, whereas ectomycorrhizal trees displayed positive feedback. Additionally, arbuscular mycorrhizal trees exhibited strong conspecific inhibition at multiple spatial scales, whereas ectomycorrhizal trees exhibited conspecific facilitation locally and less severe conspecific inhibition regionally. These results suggest that mycorrhizal type, through effects on plant-soil feedbacks, could be an important contributor to population regulation and community structure in temperate forests.

Plant-soil feedback and the maintenance of diversity in Mediterranean-climate shrublands.

Soil biota influence plant performance through plant-soil feedback, but it is unclear whether the strength of such feedback depends on plant traits and whether plant-soil feedback drives local plant diversity. We grew 16 co-occurring plant species with contrasting nutrient-acquisition strategies from hyperdiverse Australian shrublands and exposed them to soil biota from under their own or other plant species. Plant responses to soil biota varied according to their nutrient-acquisition strategy, including positive feedback for ectomycorrhizal plants and negative feedback for nitrogen-fixing and nonmycorrhizal plants. Simulations revealed that such strategy-dependent feedback is sufficient to maintain the high taxonomic and functional diversity characterizing these Mediterranean-climate shrublands. Our study identifies nutrient-acquisition strategy as a key trait explaining how different plant responses to soil biota promote local plant diversity.

Changing Security Dynamics in East Asia: A Post-US Regional Order in the Making?

Introduction: Why strategic uncertainty? Elena Atanassova-Cornelis and Frans-Paul Van der Putten PART I: EVOLVING REGIONAL SECURITY ORDER IN EAST ASIA - KEY PERSPECTIVES 1. Theoretical Approaches to Asia's Changing Security Order Nick Bisley 2. East Asian Security, Policy Debates and American Leadership Robert Sutter 3. China's Approach to the US Role in East Asia: The Dynamics of Volatile Competition Shi Yinhong PART II: EAST ASIAN RESPONSES TO STRATEGIC UNCERTAINTY 4. 'Keeping the United States In': Japan and Regional Order in East Asia Kuniko Ashizawa 5. The US Security Role in South Korea: Issues that Test South Korean Confidence in the US Commitment Larry Niksch 6. Political Resolve and Strategic Uncertainty in Taiwan-US Relations Alexis Littlefield 7. New Strategic Uncertainty and Security Order in Southeast Asia Carlyle A. Thayer PART III: ALTERNATIVE MODELS OF REGIONAL SECURITY ORDER 8. A US-China Dual Leadership in East Asia? Quansheng Zhao 9. Non-Traditional Security Cooperation and Northeast Asian Regional Order Jaewoo Choo 10. Power Bumps on the Way to Regional Community: Asia's Mixed Security Logics Alice Ba Conclusion: A post-US regional order in the making? East Asia's security futures Frans-Paul van der Putten and Elena Atanassova-Corne

Peeking into the black box: a trait-based approach to predicting plant-soil feedback.

Feedbacks between plants and soil communities may be elusive, yet they have far-reaching consequences for plant physiology, competition and community structure. Plant–soil feedbacks (PSFs) are plant-mediated changes to soil properties that ultimately influence the performance of the same or other plants (Van der Putten et al., 2013). These PSFs may be mediated by root-associated organisms (hereafter, root-mediated feedbacks) or saprotrophic organisms and associated litter characteristics (hereafter, litter-mediated feedbacks). However, we know little about the potential mechanistic linkages and relative strengths between these distinct, but connected, processes as root- and litter-mediated feedbacks have generally been studied independently from each other. This is despite the fact that root-associated organisms and saprotrophs can interact through various mechanisms, either directly or as mediated by the plant (e.g. Wardle, 2006). By using a trait-based approach,Ke et al. (in this issue of New Phytologist, pp. 329–341) make an important contribution by integrating root- and litter-mediated PSFs in a nitrogen (N)-based, stage-structured plant population and microbial community model. Their approach allows us to start peeking into the ‘black box’ thereby promoting a better understanding of how PSFs operate interactively. Ke et al. considered various plant traits (e.g. decomposability), but also incorporated trait variation in the physiology, demography and composition of the soil microbial community, and tested their separate and interactive effects on PSF strength in a comprehensive simulation framework. Finally, they used empirical evidence from the literature to support their model predictions.

Determining appropriate ambient lighting levels in Radiology reporting rooms

Determining appropriate ambient lighting levels in Radiology reporting rooms

Using Background Music to Reduce Problem Behavior during Assessment with an Adolescent who is Blind with Multiple Disabilities

Problem behaviors displayed by children with developmental disabilities include stereotypies, noncompliance, aggression, and self-injury (Griffith, Hastings, Nash, & Hill, 2010). As many as 40% of children with disabilities exhibit these behaviors (Lowe et al., 2007), with higher rates for those with visual impairments (Poppes, van der Putten, & Vlaskamp, 2010). Children who are visually impaired (that is, those who are blind or have low vision) commonly engage in stereotypic behaviors such as rocking and repetitive hand movements to gain sensory stimulation produced by the behavior (Gourgey, 1998; Rapp, 2004; Warren, 1984). A means of quickly and easily reducing problem behaviors is important to maximize individuals' learning gains and increase the accuracy of assessments. Presenting background music may quickly lower individuals' problem behavior. For instance, music was used to decrease the self-injurious behavior displayed by a boy with severe intellectual disabilities (Carey & Halle, 2002), and the vocal stereotypy of two children with autism (Lanovaz, Sladeczek, & Rapp, 2011). Moreover, in an experimental investigation of background music, Lancioni et al. (2010) found that vocal stereotypy was reduced and adaptive behavior increased in two children with visual impairments and severe disabilities. Similarly, playing background music may also improve desired behavior, such as ontask performance, with children in the classroom (Hallam & Price, 1998; Hallam, Price, & Katsarou, 2002). Robb (2003) used an experiment to demonstrate the use of background music to increase attentive behavior of preschool children with visual impairments. In contrast, other researchers have found that music may increase individuals' problem behaviors. For instance, the presence of music increased stereotypy displayed by a boy with Down syndrome and moderate intellectual disability (Rapp, 2004), and increased disruptive behaviors (ear covering and screaming) displayed by a seven-year-old boy with pervasive developmental disorder (Buckley & Newchok, 2006). Further research is needed to evaluate the use of background music to reduce problem behaviors for persons with visual impairments. Music may be a particularly salient and preferred stimulus for these individuals, given their restricted sensory input (Gourgey, 1998; Robb, 2003). Furthermore, a contrasting quiet environment may be unpleasant and may increase stereotypies, avoidance behaviors, or both. The effect of music on behaviors interfering with assessment procedures (that is, self-stimulatory behaviors and standing up) was evaluated using a single-participant research design. A comparison of background music versus no music was performed on the problem behaviors of an adolescent with visual and intellectual disabilities during an assessment. Method PARTICIPANT The participant was Yaffa, a 13-year-old girl with severe-profound intellectual disability, blindness due to bilateral congenital anophthalmia, and mild conductive hearing disorder. She can hear soft speech in a quiet room but may have difficulty in a noisy environment. Yaffa is monitored for seizure activity, which is controlled by medication (Depakote), and showed no signs of seizure during the study. Yaffa was selected to participate in the research because staff reported it was difficult to teach her new skills due to problem behaviors. She was nonverbal, and although typically compliant, cheerful, and responsive to adult attention, Yaffa would make whining sounds, stand up, or turn away in her seat to avoid tasks. Classroom observations and staff reports also indicated that Yaffa engaged in frequent stereotypies involving tapping. Following approval of the research by the Institutional Review Board at The College at Brockport, State University of New York, parental informed consent for the child's research participation was obtained. …

Southeast Asia. Melayu: The politics, poetics and paradoxes of Malayness. Edited by Maznah Mohamad and Syed Muhd Khairudin Aljunied. Singapore: NUS Press, 2011. Pp. 370. Plates, Notes, Bibliography, Index.

Melayu: The politics, poetics and paradoxes of Malayness Edited by MAZNAH MOHAMAD and SYED MUHD KHAIRUDIN ALJUNIED Singapore: NUS Press, 2011. Pp. 370. Plates, Notes, Bibliography, Index. doi: 10.1017/S0022463413000428 Is Melayu (or Malayness) a category of ethnicity? Race? Nation? Politics? Culture? Language? Geography? The answer seems to be all of the above. Melayu signifies differently in different countries of Southeast Asia, and its meanings are constantly being redefined for various ideological purposes. It can only be explored, not comprehended or defined (Maier, p. 321). Due to the confusing nature of the term it is tempting to throw up one's hands (and some scholars have!). Nevertheless the field of Malay studies has expanded recently, with several books, articles, and special issues of journals published in the last decade. The difficulty of defining Melayu does not diminish its significance; rather, the problematic nature of the term is precisely the reason for its continued interrogation. To the scholars who have thrown up their hands, Malayness as an ethnic category is no more problematic than any other ethnic category. And the stakes are high. Malayness as a marker of ethnic identity signifies everyday struggles over the nature and practice of citizenship, community, and rights. The essays in this book attempt to move the question away from the primordialist colonial discourse about 'who or is (a) Malay?' to Malayness as a discursive practice: 'Who (defines) Malayness?' and 'When was (is) Malayness used as a category for grouping people together and for what ideological purposes?' The authors do not ignore primordialist claims, but interrogate them as constructed categories in particular social contexts: 'Who gets to enjoy the privileged status of Malayness and who is excluded from those privileges?' These questions are deeply grounded in historical and material contexts: 'What conditions made it possible to think about being Malay in particular ways and not others?' The introduction ably demonstrates that Malayness cannot be conceptualised as a single entity. For example, the book begins with three epigraphs from different historical periods and geographical locations, in which Malayness is represented in terms of race, kinship, and nationhood. The solution to understanding Melayu, as proposed by the editors Maznah Mohamad and Syed Muhd Khairudin Aljunied, is to 'view Melayu as a signifier that brings to mind a whole array of associations--places, languages, families, communities, nation-states, cultural symbols, events, texts, collectives, political parties and religious beliefs' (p. xiv). The book constitutes twelve chapters arranged in four geographical areas: Malaysia (5), Singapore (3), Indonesia and the Philippines (2), and across nations (2). Melayu does not circumscribe a geographical place, but it does take place in specific places. Further, although the latter two chapters are subsumed within the 'across nations' section, several other chapters deal with trans-local topics (for example, the chapters by Aljunied, van der Putten, and Curaming). In addition to the geographic organisation of chapters, the book emphasises three 'dimensions which illuminate the various associations by which Malayness is built upon': politics, poetics, and paradoxes (p. xv). These 'dimensions' intersect and so it is difficult to pinpoint exactly which chapters align with which dimensions. Politics refers to not only who is granted privileges based on being defined as Malay (for example, in Malaysia, where Malays are 'first among equals'), but also the institutions that grant 'the right to define and determine the boundaries of Malayness' (p. xv). Poetics refers to narratives of Malayness in colonial texts and contemporary novels and poetry. Politics and poetics are deeply imbricated: discourses about Melayu are expressed in different ways according to historical and political contexts, and forms of expression can be mined for political meanings. …

Regulation of Metabotropic Glutamate Receptor 7 (mGluR7) Internalization and Surface Expression by Ser/Thr Protein Phosphatase 1

The metabotropic glutamate receptor type 7 (mGluR7) is the predominant group III mGluR in the presynaptic active zone, where it serves as an autoreceptor to inhibit neurotransmitter release. Our previous studies show that PKC phosphorylation of mGluR7 on Ser-862 is a key mechanism controlling constitutive and activity-dependent surface expression of mGluR7 by regulating a competitive interaction of calmodulin and protein interacting with C kinase (PICK1). As receptor phosphorylation and dephosphorylation are tightly coordinated through the precise action of protein kinases and phosphatases, dephosphorylation by phosphatases is likely to play an active role in governing the activity-dependent or agonist-induced changes in mGluR7 receptor surface expression. In the present study, we find that the serine/threonine protein phosphatase 1 (PP1) has a crucial role in the constitutive and agonist-induced dephosphorylation of Ser-862 on mGluR7. Treatment of neurons with PP1 inhibitors leads to a robust increase in Ser-862 phosphorylation and increased surface expression of mGluR7. In addition, Ser-862 phosphorylation of both mGluR7a and mGluR7b is a target of PP1. Interestingly, agonist-induced dephosphorylation of mGluR7 is regulated by PP1, whereas NMDA-mediated activity-induced dephosphorylation is not, illustrating there are multiple signaling pathways that affect receptor phosphorylation and trafficking. Importantly, PP1γ1 regulates agonist-dependent Ser-862 dephosphorylation and surface expression of mGluR7.